The goal of our proposed research is to increase our understanding of the factors leading to the interrelationship between atherosclerosis and hypertension. Using a combination of mechanical and genetic manipulations in a mouse model of atherosclerosis, we will assess the relative influence on atherogenesis of direct physical changes in blood pressure versus genetic changes in systemic vasoactive mediators or in the factors that affect local responsiveness of vascular tissues. Specific aim (i) is to determine the effects at different stages of lesion development in the carotid arteries of a superimposed mechanical increase (right) or decrease (left) in pressure consequent to aortic arch coarctation. Specific aim (ii) is to determine whether the effects observed above can also be achieved by blood pressure changes as a consequence of genetically controlled changes in the expression of the systemic vasoactive mediator, renin. Specific aim (iii) is to determine the effects of mechanically-imposed changes in pressure on lesions in the carotid arteries of proatherogenic mice with additional genetic mutations that have local effects on vascular tissues via three different systems: (a) angiotensin II receptor type 1A, (b) endothelial nitric oxide synthase, and (c) natriuretic peptide receptor A. Better understanding of the effects on atherogenesis of the individual factors that affect blood pressures should help the development of new means for prevention and treatment of cardiovascular diseases.